PROJECT SUMMARY Exercise is one of the most powerful tools to prevent muscle loss and aging-related diseases. Reactive oxygen species (ROS) and inflammation, long-thought to contribute to tissue damage, have recently been recognized to function as signaling molecules necessary for the benefits of exercise. My preliminary data demonstrate that improved glucose tolerance and exercise capacity, two hallmarks of exercise-induced muscle adaptation, are attenuated in mice deficient in NADPH oxidase 4 (Nox4), an ROS-producing enzyme. My data indicate that Nox4 drives an Nlrp3 muscle cytokine response that leads to improved muscle metabolism. In this proposal, I will investigate the role of redox-mediated adaptation to exercise using state-of-the art techniques in immunology and muscle physiology (e.g., Amnis/Immagestream, RNA-seq, and ex vivo muscle stimulation). To aid me in completion of this project, I have established a strong mentoring team comprised of experts in the fields of inflammation and immunology (Dr. Katherine Fitzgerald), muscle molecular biology and regeneration (Dr. Charles Emerson), skeletal muscle adaptation to exercise and redox signaling (Dr. Zhen Yan) and immunometabolism (Dr. Michael Czech), all of whom are top leaders in their respective fields and have lengthy track records of mentoring success. My career goal is to lead a successful research program dedicated to the investigation of redox and inflammatory signaling in angiogenesis and skeletal muscle adaptation. I believe that the knowledge gained by understanding the details of ROS signaling in adaptation to exercise will lead to the development of better therapeutic strategies to combat frailty, diabetes, obesity, and musculoskeletal diseases.